Through binding to cellular receptors, the viral capsid (a) will determine the tropism of the RNAi vector, i.e., the tissue and cell type that will be infected. This occurs regardless of the vector insert. In a conventional shRNA expression cassette (i), the promoter (b) can further contribute to specificity by being active only in desired tissue or cell types. Alternatively, promoters can be made regulatable via exogenous triggers. Ideally, both properties are combined to permit spatiotemporal control over shRNA expression. Moreover, the shRNA itself (c) is a major determinant of specificity and control and should be designed to selectively bind to the target mRNA. (ii) Theoretically, it should be possible to create hybrid vector genomes in which an shRNA cassette is fused with a binding site for a particular miRNA (d; black box). This would allow the restriction of shRNA expression only to cells in which this miRNA is not expressed, thus helping to minimize off-target effects. (iii) Alternatively, the hybrid genome (or a vector expressing a cDNA; green box) could be fused with multiple tandem sites for miRNA binding and then be used to sequester, and thus inactivate, this miRNA from the cellular pool. This strategy is useful to block miRNAs that are involved in pathogenic processes such as tumorigenesis.